18-oxygenated-delta-3,20-dioxo-9alpha-halopregnenes



"str'ate valuable physiological activities.

1S-OXYGENATED-A -3,20-DIXO-9a-HALO- PREGNENES Albert Wettstcin and GeorgAnner, Basel, Switzerland,

assignors to Cilia Pharmaceutical Products, Inc., Summit,N.J.

No Drawing. Application May 18, 1955 Serial No. 509,391

Claims priority, application Switzerland May 25, 1954 12 Claims. (Cl.260-23955) This invention relates to 11,18,21 trioxygenated Especiallyvaluable are the aforesaid compounds wherein littlogenois chlorine orfluorine.

The novel compounds of the present invention demon- They possesssuprarenal cortex hormone activity'and can be employed in'the treatmentof adrenal cortical insufiiciency. The

new compounds can be administered in any suitable dosage :form, in thesame manner as hydrocortisone, cortisone, *aldosterone ordesoxycorticosterone.

The novel compounds in which the halogeno radical 'is bromine arereadily prepared by converting 18,21-dioxygen'ated A 3-3,20-dioxo-pregnadienes, preferably ii! the form'of the esters thereofinto 18,2l-dioxygenated A -3,20-dioxo-9a-bromo-1lfl-hydroxy-pregnenes,for example, by treating the former with N-bromacetamideorN-brorn'osuccinimide, preferably in the presence of a catalyst, such 'assulfuric acid. The 9a-bromo- 1lB-hydroxy compounds can then be convertedvia 18,21-dioxy- 'ing agent, that is, an agent which splits off hydrogenbromide, to form A 3,2 0-dioxo-9,llB-oxido-l8,2'l-di-'a'cctoxy-pregnene, which is then treated with hydrogen chloride toproduce A 3,20-dioxo9ot-chloro-1lit-hydroxy- 18,2'1-diacetoxy pregnene,or with hydrogen fluoride to produce A 3,20 dioxo 90c fluoro 11 8:hydroxy- I 18,2l-diacetoxy pregnene. When'hydrogen iodide is employedthere is obtained A-3,20-dioxo-9a-iodo-11,8-hydroxy-18,21-diacetoxy-pregnene.

As dehydrobrominating agents there can be employed advantageouslyhydroxides or oxides of metals of the first and second groups of theperiodic system, for example, silver oxide, and also tertiary bases suchas pyridine or collodine, or aluminum oxide. It is of advantage to usetertiary bases in combination with one of the aforesaid monovalent ordivalent metal hydroxides or oxides.

By hydrolysis of the A -3,20-dioxo-19,11fi-oxido-18,21-dihydroxy-pregnene-l8,21-diesters, selective esterification in2l-position and dehydrognation in 18-position there are obtained A3,18,20 trioxo 9,11,6 oxido 21 hydroxy-pregnene-Zl-esters which can beconverted by the action of a hydrogen halide into the A -3,18,20-trioxo-11fi-hydroxy-9a-halogeno-pregnene-M-esters. The hydrolysis,esterification and dehydrogenation steps are carried out in knownmanner.

'- cc. of 2.5 'N-hydrochloric-acid,:and-the whdle-isalldwed The novel18,21-dioxygenated A -3,2O-dioxo-pregn'adienes employed as startingmaterials can be prepared by known methods, for example by splitting offwater from 18,21 dioxygenated A 3,20 dioxo 11B hydroxy-pregnenes with adehydrating agent, e.g., phosphorus oxychloride in the presence of abase such as pyridine. In this way A -3,20-dioxo 11B,18,21-trihy droxypregnene yields A 3,20 dioxo 18,21- dihydroxy-pregnadiene, which isesterified to produce the 18,21-diacyloxy compounds.

The novel compoundscan be employed in combination with any suitablecarrier to facilitate the administration thereof.

The following examples will serve to illustrate the preparation of thenovel compounds.

Example 1 A solution of 170 milligrams of A -3,20-dioXo-18,2l-diacetoxy-pregnadiene in 4.5 cc. of tertiary butanol and 1 cc. 'ofwater is mixed, While stirring, at about 15 C. with 120 milligrams ofN-bromacetamide and 1 cc. of sulfuric acid of 4 percent strength. Aftera few minutes the reaction solution becomes yellow-brown. For thepurposeof decolorization an aqueous 1 percent solution of sodium sulfiteand 50 cc. of Water are then added, the mixture is extracted with amixture of chloroform and ether 1:3) and the extract is washed severaltimes with an ice-cold 1 percent sodium carbonate solution and water. Byevaporating the dried chloroform-ether solution in vacuo there isobtained A -3,2O-dioxo-9e -'bromo- "1l,8-'hydroxy-18,2l-diacetoxy-pregnene.

A solution of 110 milligrams of the aforesaid A -3,20- dioxo c bromo11,8 hydroxy 18,21 diacetoxypregnene in 2 cc. of anhydrous pyridine isagitated with 150 milligrams of freshly precipitaed and dried silveroxide for 24 hours in the dark. The silver oxide is then filtered offwith suction, and the filtrate is evaporated in vacuo. For the purposeof re-acetylating the A 320-dioxo-9,-11,8-oxido-18,2l-dihydroxy-pregnene thus formed,

the residue is dissolved in '1 cc. of pyridine andOJS cc.

of acetic 'anhydride, and the whole is allowed to stand for 14 hours atroom temperature. The mixture is then sulfuric acid, sodium bicarbonatesolution and water. After drying and evaporating the chloroform-ethersolu- "tion in vacuo, there is obtained A -3,20-dioxo-9,11fioxido-18,21-diacetoxy-pregnene.

milligrams of the above 19,11-Oxido-compound are dissolved in 10 cc. ofdioxane, then mixed With 2. 5

to stand for one hour at room temperature. 'Water'is then added and thewhole is extracted with a mixture of chloroform and ether (1:3). Bywashing the extract with Water, drying it and evaporating the solvent invacuo, there is obtained A -3,2O-dioxo-9a-chloro-1Iii-hydroxy-18,21-diacetoxy-pregnene.

By reacting the A -3,20-dioxo-9,11/8-oxitlo-1S,21diacetoxy-pregnene inthe same manner with hydrofluoric acid, there is obtained A-3,20-dioxo-9c-fiuoro-1lfi-hydroxy-18,21-diacetoxy-pregnene.

The A -3:20-dioxo-18,2l-diacetoxy-pregnadiene used as starting materialcan be prepared, for example, as follows:

1 gram of A -3,20-dioxo--18,21,trihydroxy-pregnene (prepared for exampleas described in application Ser. No. 480,061, filed January 5, 1955, byreduction of A 3,20 diethylenedioxy 115,21 dioxy 18 oxopregnene withlithium aluminium hydride followed by hydrolysis of the ketal groups isdissolved in 10 cc. of pyridine, the solution is cooled in a mixture ofice and sodium chloride and 1 gram of phosphorus oxychloride is addeddropwise. After allowing the whole to stand for 14 hours at roomtemperature, it is poured on to ice and the-3,20-dioxo-18,2l-dihydroxy-pregnadiene is extracted, which is thenconverted into A -3,20-dioxo-l8,2l-diacetoxy-pregnadiene by acetylationwith 10 cc. of acetic anhydride and 10 cc. of pyridine.

Example 2 To a solution of 80 milligrams of A -3,20-dioxo-9,11B-oxido-18,21-diacetoxy-pregnene in 15 cc. of methanol there are added 100milligrams of potassium bicarbonate in 3.5 cc. of water. The reactionmixture is kept for 48 hours at 20 C., then concentrated in vacuo. Theresidue still containing water is extracted with chloroform-ether (1:3).After washing the extract with water, the solvents are dried andevaporated. The residue, A-3,20-dioxo-9,1lp-oxido-l8,21-dihydroxy-pregnene, is dissolved in 1.5cc. pyridine. After addition of 1 cc. acetic anhydride at C. the mixtureis kept at 25 C. for 2 days and then extracted with ether. The etherealextract is washed with 1 percent hydrochloric acid, water, 2 percentsodium bicarbonate solution and water, and dried and evaporated to yieldA -3,20-dioxo- 9,-1lfl-oxido-18-hydroxy-2l-acetoxy-pregnene.

To a solution of 100 milligrams of chromic acid in 5 cc. of pyridine areadded at 0 C. 55 milligrams of A 3,20 dioxo 9,11fl oxidoacetoxy-pregnene. The mixture is kept at room temperature for 20 hoursand then concentrated in vacuo. The residue is treated with ice andwater and extracted .with methylene chloride. After washing themethylene .chloride solution with 1 percent hydrochloric acid and waterthe solution is dried and evaporated in vacuo.

.The residue is A -3,18,20-trioxo-9,1lfl-oxido-Zl-acetoxypregnene.

A solution of 20 milligrams of A -3,18,20-tr1oxo 9,

trihydroxy 9an'ihydroxy 9oztrioxo 11,21 dihydroxy 9a- 18 hydroxy 21-- in2 cc. of dioxane is Y t 4 4. A 3,18,20 trioxo 11,21 dihydroxy9afluoro-pregnene.

5. A 3,20 dioxo 9,1118 oxido 18,21 dihydroxypregnene.

6. A -3,18-20-trioxo-9,1lfl-oxido-Zl-hydroxy-pregnene. 7. A compound ofthe formula:

in which formula R represents a member selected from the groupconsisting of a free hydroxymethyl group, a hydroxymethyl groupesterified with a lower aliphatic carboxylic acid and a free aldehydegroup, R represents a member selected from the group consisting of afree hydroxyl group and a hydroxyl group esterified with a loweraliphatic carboxylic acid and X is a halogen atom.

8. A 3,20 dioxo 9a fluoro 1118 hydroxy- 18 ,2 1 -diacetoxy-pregnene.

9. A 3,20 dioxo 9oz chloro 1113 hydroxy, 18,21-diacetoxy-pregnene.

10. A 3,18,20 trioxo 9a chloro 11,8 hydroxy- 2l-acetoxy-pregnene.

11. A 3,18,20, trioxo 9a fiuoro 1113 hydroxy- 21-acetoxy-pregnene.

12. A compound of the group consisting of A -3,20- dioxo 9,1118 oxido18,21 dihydroxy pregnenes, A -3,18,20-trioxo-9, l 1fi-oxido-Zl-hydoxy-pregnenes, 21- monoesters of these compounds and18,21-diesters of the A 3,20 dioxo 9,115 oxido 18,21 dihydroxypregnenes,said esters being formed with lower aliphatic carboxylic acids.

References Cited in the file of this patent UNITED STATES PATENTS2,596,563 Kaufman May 13, 1952 2,597,190 Sarett May 20, 1952 2,673,849Spero Mar. 30, 1954 2,686,181 Julian Aug. 10, 1954 2,703,799 BergstromMar. 8, 1955 2,773,080 Bernstein Dec. 4, 1956 OTHER REFERENCES UNITEDSTATES PATENT OFFICE Certificate of Correction Patent No. 2,917,510December 15, 1959 Albert Wettstein et al.

It is hereby certified that error appears in the printed specificationof the above numbered satent requiring correction and that the saidLetters Patent should read as correcte below.

Column 1, line 4:3, for -11,28,21- read -11,18,21-; line 64:, for-dioxo-19, read --dioXo-9,; column 2, line 35, for precipitaed readprecipitated; line 65, for -11,8-18,2l,trihydroxypregnene" read-11,8,18,21-trihydr0xy-pregnene,-; same column 2, line 70, for groups isread groups) is; column 3, line 4:, for -3,20 read A -3,20- line 24,strike out and, first occurrence; column 4, line 5, for 18-20 read--l8,20-; line 25, for hydroxy, read -hydr0xyline 29, for -3,18,20, read-3,18,20-

Signed and sealed this 13th day of December 1960.

Attest: KARL H. AXLINE, ROBERT C. WATSON, v Attestz'ng Ofiicer.Commissioner of Patents.

7. A COMPOUND OF THE FORMULA:
 12. A COMPOUND OF THE GROUP CONSISTING OF$43,20DIOXO - 9,11B - OXIDO - 18,21 - DIHYDROXY - PREGNENES,$4-3,18,20-TRIOXO-9,11B-OXIDO-21-HYDROXY-PREGNENES, 21MONOESTERS OFTHESE COMPOUNDS AND 18,21-DIESTERS OF THE $4 - 3,20 - DIOXO - 9,11B -OXIDO - 18,21 - DIHYDROXYPREGNENES, SAID ESTERS BEING FORMED WITH LOWERALIPHATIC CARBOXYLIC ACIDS.